Abstract
Modern medicine is challenged by several potentially severe fungal pathogens such as Aspergillus fumigatus, Candida albicans, or Histoplasma capsulatum. Though not all fungal pathogens have evolved as primary pathogens, opportunistic pathogens can still cause fatal infections in immuno-compromised patients. After infection with these fungi, the ingestion and clearance by innate immune cells is an important part of the host immune response. Innate immune cells utilize two different autophagic pathways, the canonical pathway and the non-canonical pathway, also called microtubule-associated protein 1A/1B-light chain 3 (LC3) -associated pathway (LAP), to clear fungal pathogens from the intracellular environment. The outcome of autophagy-related host immune responses depends on the pathogen and cell type. Therefore, the understanding of underlying molecular mechanisms of autophagy is crucial for the development and improvement of antifungal therapies. One of those molecular mechanisms is the interaction of the transcription-factor hypoxia-inducible factor 1α (HIF-1α) with the autophagic immune response. During this review, we will focus on a comprehensive overview of the role of autophagy and HIF-1α on the outcome of fungal infections.
Highlights
During the last years, the significance of autophagy to the innate immune response against fungal infections has become evident
The widespread and increasing use of biologicals and immunosuppressive therapies facilitate the emergence of potentially severe, fungal infections such as Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Histoplasma capsulatum
Autophagy was understood as a self-catabolic process to counteract nutritional starvation
Summary
The significance of autophagy to the innate immune response against fungal infections has become evident. Initiation of autophagy leads to an increase in released NETs [16] Some fungal pathogens, such as Aspergillus fumigatus, can be recognized upon first contact with the immune cell and the non-canonical autophagy pathway, called the LAP-pathway, is triggered. Several studies have shown the activation of autophagy downstream of HIF-1α [5,27], suggesting a positive feedback loop in which autophagy is needed to generate energy to support the innate immune response while HIF-1α modulates the cell metabolism as part of the immune response This transcription factor induces a series of alterations in macrophages (MΦ), including increases in inflammatory cytokines, chemokines, and antimicrobial peptides. We will take a closer look at the impact of HIF-1α regulation on the outcome of antifungal immune responses as part of the LAP-pathway
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